Roflumilast (CAS 162401-32-3) is a member of a class of fluoroalkoxy-substituted benzamides developed by BYK Gulden Lomberg Chemische Fabrik GmbH. See U.S. Pat. No. 5,712,298 to Hermann Amschler. The compounds are indicated to be useful as phosphodiesterase inhibitors. Roflumilast itself is an once-daily oral phosphodiesterase inhibitor in phase III trials to treat asthma and pulmonary obstructive disease. Another indication of dermatitis is still in preclinical stage. The chemical name of roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloro4-pyridiny)-4-(difluoromethoxy)benzamide.
The best known published route to roflumilast and its congeners is a six-step process with an overall yield of only 4 percent. Another previously-known synthetic route is a five-step procedure involving a Reimer-Tiemann reaction. Attempts to carry out this synthetic route failed; the particular Reimer-Tiemann reaction could not be reproduced.
A need exists for a practical process for production of roflumilast and its congeners capable of forming the products in good overall yields using available starting materials.
This invention is deemed to fulfill this need in an efficient manner.
3,4-Disubstituted benzoic acid esters, 3,4-disubstituted benzoic acids, and 3,4-disubstituted benzoyl chlorides or bromides, in which the substituent in the 3-position, R1, is a C1-6 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, or benzyloxy group, or a C1-4 alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R2, is a C1-4 alkoxy group which is completely or partially substituted by fluorine, are useful intermediates for the preparation of many of the fluoroalkoxy-substituted benzamides described in U.S. Pat. No. 5,712,298 to Hermann Amschler. This invention thus provides, inter alia, processes for the preparation of such 3,4-disubstituted benzoic acid esters, 3,4-disubstituted benzoic acids, and 3,4-disubstituted benzoyl chlorides or bromides.
This invention provides a process for the preparation of a 3,4-disubstituted benzoyl compound in which the substituent in the 3-position, R1, is a C1-6 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, or benzyloxy group, or a C1-4 alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R2, is a C1-4 alkoxy group which is completely or partially substituted by fluorine, which process comprises:
A) alkylating an ortho-R1-substituted para-halophenol in which the para-halo substituent is a chloro, bromo, or iodo substituent with an alkylating agent which is a C1-4 monobaloalkane in which the halo substituent is chloro, bromo, or iodo, and in which said monohaloalkane is otherwise completely or partially substituted by fluorine, to form a product comprised of a 1-halo-3,4-disubstituted benzene in which the substituent in the 3-position is R1, and in which the substituent in the 4-position is R2;
B) carbonylating 1 -halo-3,4-disubstituted benzene from A) with carbon monoxide to form a product comprised of a 3,4-disubstituted benzoyl compound in which the substituent in the 3-position is R1, and in which the substituent in the 4-position is R2.
In further embodiments, 3,4-disubstituted benzoyl compound from B) is converted using aniline, 4-aminopyridine, aniline which is substituted by R31, R32, and R33, or 4-aminopyridine which is substituted by R34, R35, R36, and R37 wherein:
R31, is hydroxyl, halogen, cyano, carboxyl, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyl, C1-4 alkylcarbonyloxy, amino, mono- or di-C1-4 alkylamino or C1-4 alkylcarbonylarmino;
R32 is hydrogen, hydroxyl, halogen, amino, trifluororethyl, C1-4 alkyl, or C1-4 alkoxy;
R33 is hydrogen, halogen, amino, C1-4 alkyl, or C1-4 alkoxy;
R34 is hydroxyl, halogen, cyano, carboxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or amino;
R35 is hydrogen, halogen, amino, or C1-4 alkyl;
R36 is hydrogen or halogen; and
R37 is hydrogen or halogen;
into a product comprised of the resultant 3,4-disubstituted benzamide.
A preferred embodiment of this invention is a process for the preparation of a 3,4-disubstituted benzoic acid ester in which the substituent in the 3-position, R1,is a C1-6 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, or benzyloxy group, or a C1-4 alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R2, is a C1-4 alkoxy group which is completely or partially substituted by fluorine, which process comprises:
A) alkylating an ortho-R1-substituted para-halophenol in which the para-halo substituent is a chloro, brormo, oriodo substituent with an alkylating agent which is a C1-4 monohaloalkane in which the halo substituent is chloro, bromo, or iodo, and in which said monohaloalkane is otherwise completely or partially substituted by fluorine, to form a product comprised of a 1-halo-3,4-disubstituted benzene in which the substituent in the 3-position is R1, and in which the substituent in the 4-position is R2;
B) carbonylating 1-halo-3,4-disubstituted benzene from A) with carbon monoxide under alkaline conditions and in the presence of an alcohol to form a product comprised of a 3,4-disubstituted benzoic acid ester in which the substituent in the 3-position is R1, and in which the substituent in the 4-position is R2.
A preferred way of converting the 3,4-disubstituted benzoyl compound formed in B)xe2x80x94in this particular case a 3,4-disubstituted benzoic acid esterxe2x80x94to the desired 3,4-disubstituted benzamide comprises hydrolyzing 3,4-disubstituted benzoic acid ester from B) to the corresponding 3,4-disubstituted benzoic acid. 3,4-Disubstituted benzoic acid formed by the hydrolysis can be readily converted to the corresponding 3,4-disubstituted benzoyl chloride or bromide, for example by reaction with SOCl2 or SOBr2. Such 3,4-disubstituted benzoyl chloride or bromide can then be amidated with aniline, 4-aminopyridine, aniline which is substituted by R31, R32, and R33, or 4-aminopyridine which is substituted by R34, R35, R36, and R37, wherein R31, R32, R33, R34, R35, R36, and R37 are as described above, to form a product comprised of the resultant 3,4-disubstituted benzamide.
Another of the preferred embodiments of this invention is a process for the preparation of a 3,4-disubstituted benzoic acid ester in which the substituent in the 3-position, R1,is a C1-6 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, or benzyloxy group, or a C1-4 alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R2, is a C1-4 alkoxy group which is completely or partially substituted by fluorine, which process comprises:
a) halogenating (i) an ortho-R1-substituted phenol to form a product comprised of (ii) an ortho-R1-substituted para-halophenol in which the para-halo substituent of (ii) is a chloro, bromo, or iodo substituent;
b) alkylating ortho-R1-substituted para-halophenol from a) with an alkylating agent which is a C1-4 monohaloalkane in which the halo substituent is chloro, bromo, or iodo, and in which said monohaloalkane is otherwise completely or partially substituted by fluorine, to form a product comprised of (iii) a 1-halo-3,4-disubstituted benzene in which the substituent in the 3-position is R1, and in which the substituent in the 4-position is R2;
c) carbonylating 1-halo-3,4-disubstituted benzene from b) with carbon monoxide under alkaline conditions and in the presence of an alcohol to form a product comprised of (iv) an 3,4-disubstituted benzoic acid ester in which the substituent in the 3 -position is R1, and in which the substituent in the 4-position is R2.
As noted above, 3,4-disubstituted benzoic acid ester formed in the carbonylation reaction can readily be hydrolyzed to the corresponding 3,4-disubstituted benzoic acid. Also 3,4-disubstituted benzoic acid formed by the hydrolysis can be readily converted to the corresponding 3,4-disubstituted benzoyl chloride or bromide, for example by reaction with SOCl2 or SOBr2. And as also noted above, such 3,4-disubstituted benzoyl chloride or bromide can then be amidated with aniline, 4-aminopyridine, aniline which is substituted by R31, R32, and R33, or 4-aminopyridine which is substituted by R34, R35, R36, and R37, wherein R31, R32, R33, R34, R35, R36, and R37 are as described above, to form a product comprised of the resultant 3,4-disubstituted benzamide.
Also provided by this invention is a process for the preparation of fluoroalkoxy-substituted benzamides, which process comprises:
a) halogenating (i) an ortho-substituted phenol to form a product comprised of (ii) an ortho-substituted para-halophenol, said substituent in the ortho position of (i) and (ii) being R1 wherein R1 is a C1-6 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, or benzyloxy group, or a C1-4 alkoxy group which is completely or partially substituted by fluorine, and the para-halo substituent of (ii) is a chloro, bromo, or iodo substituent;
b) alkylating ortho-substituted para-halophenol from a) with an alkylating agent which is a C1-4 monohaloalkane in which the halo substituent is chloro, bromo, or iodo, and in which said monohaloalkane is otherwise completely or partially substituted by fluorine, to form a product comprised of (iii) a 1-halo-3,4-disubstituted benzene in which the substituent in the 3-position is R1, and in which the substituent in the 4-position is R2 wherein R2 is a C1-4 alkoxy group which is completely or partially substituted by fluorine;
c) carbonylating 1-halo-3,4-disubstituted benzene from b) with carbon monoxide under alkaline conditions and in the presence of an alcohol to form a product comprised of (iv) an 3,4-disubstituted benzoic acid ester in which the substituent in the 3-position is R1, and in which the substituent in the 4-position is R2, and hydrolyzing said ester to the corresponding 3,4-disubstituted benzoic acid;
d) converting 3,4-disubstituted benzoic acid ester from c) to (v) 3,4-disubstituted benzoyl chloride or bromide; and
e) amidating 3,4-disubstituted benzoyl chloride or bromide from d) with aniline, 4-aminopyridine, aniline which is substituted by R31, R32, and R33, or 4-aminopyridine which is substituted by R34, R35, R36, and R37 wherein R31, R32, R33, R34, R35, R36, and R37 are as described above, to form a product comprised of the resultant 3,4-disubstituted benzamide.
Novel key intermediates making possible the process technology of this invention are o-(cycloalkylmethoxy)-p-halophenols in which the cycloalkylmethoxy group is a C3-7 cycloalkylmethoxy group, and in which the halo substituent is a chlorine, bromine or iodine atom, especially o-(cyclopropylmethoxy)-p-bromophenol, and 1-halo-3,4-disubstituted benzenes in which the halo substituent in the 1-position is a chlorine, bromine, or iodine atom, in which the substituent in the 3-position, R1, is a C1-6 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, or benzyloxy group, or a C1-4 alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R2, is a C1-4 alkoxy group which is completely or partially substituted by fluorine, especially 1-bromo-3-(cyclopropylmethoxy)-4-difluoromethoxybenzene.
Another embodiment of this invention is a process which comprises converting a 1-halo-3-R1-4-R2-substituted benzene in which the R1 and R2 substituents are as described above, and in which the halo substituent is a chlorine, bromine or iodine atom, to a 3-R1-4-R2-substituted benzamide in which the amide functionality has the formulaxe2x80x94CONHR, where R is a phenyl group optionally substituted by R31, R32, and R33, or a 4-pyridyl group optionally substituted by R34, R35, R36 and R37, where R31, R32, R33, R34, R35, R36 and R37 are as described above. There are various ways by which this conversion can be accomplished. One way is a process which comprises:
1) subjecting a 1-halo-3-R1-4-R2-substituted benzene in which the R1 and R2 substituents are as described above, and in which the halo substituent is a chlorine, bromine or iodine atom, to carbonylation to form a 3-R1-4-R2-substituted benzene in which the 1-position contains carboxy functionality, and optionally transforming the carboxy functionality, such that there is produced a product comprised of (i) a 3-R1-4-R2-substituted benzoic acid ester, (ii) a 3 -R1-4-R2-substituted benzoic acid, (iii) an alkali or alkaline earth metal salt of a 3-R1-4-R2-substituted benzoic acid, or (iv) a 3-R1-4-R2-substituted benzoyl chloride or bromide; and
2) amidating (i), (ii), (iii) or (iv), or a mixture of any two or more of (i), (ii), (iii) and (iv) with aniline, 4-aminopyridine, aniline which is substituted by R31, R32, and R33, or 4-aminopyridine which is substituted by R34, R35, R36, and R37, wherein R31, R32, R33, R34, R35, R36, and R37 are as described above, to form a product comprised of the resultant 3,4-disubstituted benzamide.
The carboxy functionality referred to in 1) above is an esterified carboxyl group (xe2x80x94COORxe2x80x2), a carboxyl group (xe2x80x94COOH), a carboxyl group that has been metal cation (xe2x80x94COOM or xe2x80x94COOM0.5), or a carbonyl chloride or carbonyl bromide group (xe2x80x94COCl or xe2x80x94COBr). Thus the transforming of the carboxy functionality referred to in 1) above means converting one such carboxy functionality to another such carboxy functionality, which conversions are within the knowledge and skill of those of ordinary skill in the art.
Another way of effecting the conversion of a 1-halo-3-R1-4-R2-substituted benzene to a 3-R1-4-R2-substituted benzamine in which the amide functioality has the formula xe2x80x94CONHR is a process which comprises subjecting a 1 -halo-3-R1-4-R2-substituted benzene in which the R1 and R2 substituents are as described above, and in which the halo substituent is a chlorine, bromine or iodine atom, to carbonylation in the presence of aniline, 4-aminopyridine, aniline which is substituted by R31, R32, and R33, or 4-aminopyridine which is substituted by R34, R35, R36, and R37, wherein R31, R32, R33, R34, R35, R36, and R37 are as described above, to form a product comprised of the resultant 3,4-disubstituted benzamide. Conditions that may be used for carrying out this reaction are referred to in A. Schoenberg and R. F. Heck, J. Org. Chem., 1974, 39, 3327. See also Example 5, infra.
Other embodiments and features of this invention will be still further apparent from the ensuing description and appended claims.